ABSTRACT Plasmodium falciparum infection continues to cause worldwide morbidity and mortality in endemic regions. P. falciparum can result in cerebral malaria (CM) in travelers and in residents of endemic regions. CM is associated with a high mortality rate due to severe brain swelling and herniation. Brain swelling as a complication of an infectious disease is unique and may point to a parasite etiology. The brain swelling is often diffuse and rapidly reversible suggestive of a circulating factor. To discover a parasite role in CM brain swelling we carried out an association study of parasite transcripts with brain swelling measured by neuro magnetic resonance imaging during CM from Malawian children. We identified a P. falciparum parasite gene transcript (PfPLA2-1) to be associated with brain swelling, and in the related apicomplexa, Toxoplasma, a PLA2 has been demonstrated to mediate brain inflammation and survival in the animal model. We will test the hypothesis that malaria PLA2 pathway metabolites damage endothelial cells to result in increased brain permeability. Our specific aims will address the role of malaria PLA2 in brain permeability and its effect on brain endothelial cell activation and apoptosis. Aim 1 will test if the PfPLA2-1's orthologue in P. berghei ANKA mediates blood brain barrier (BBB) permeability using the animal model of experimental cerebral malaria and test the effect of a mammalian PLA2 inhibitor in this system. Malaria parasites co-cultured with endothelial cells can damage them and increase endothelial cell monolayer permeability. We will examine the role of PfPLA2-1 on endothelial cell activation. Aim 2 will employ a PfPLA2-1 knock down in the in vitro P. falciparum culture system using 3' gene editing methods to determine if PfPLA2-1 mediates endothelial cell activation and apoptosis in the co-culture model. These studies will provide data for a future R01 to develop adjunctive therapy to reduce brain permeability and improve CM outcomes.